The long-term objective is to understand the mechanisms for acute and delayed toxicity from important organophosphorous (OP) and phosphine insecticides. These compounds are major concerns for human health since they are widely used in agriculture and responsible for more cases of poisoning than any other pesticide class. The first aim is to define the mechanisms of OP-induced delayed toxicity (which has afflicted greater than 30,000 people) associated with neuropathy target esterase (NTE) using our newly-developed radioligand [3H]OBDPO and a novel carbamate-biotin affinity agent for target isolation from hen brain in active form of structural and functional characterization. Non-NTE targets phosphorylated by [3H]OBDPO and radioligands based on other OP delayed toxicants will be identified as with NTE itself. Cellular models will determine OP-induced changes in neural growth, essential neurotropic factors and ion transport. The second aim is to understand the mechanisms of important OP insecticides because of systemic action in plants and moderate toxicity to mammals. The hypotheses are: acephate toxicity is self-limiting because its metabolite methamidophos inhibits the amidase that activates acephate; methamidophos is bioactivated by S-oxidation (old hypothesis) or N-oxidation (new proposal) requiring studies of chemical models to resolve the site and stability relationships; S-methylation of dimethyl phosphorodithioic acid as a dimethoate metabolite contributes to its toxicological profile including delayed effects. The third aim is to establish the mechanisms for toxicity of aluminum phosphide which is increasingly replacing methyl bromide (the ozone depleter) as the major fumigant for stored products. The overall hypothesis is that 1) phosphine, a gas liberated on environmental hydrolysis of aluminum phosphide, undergoes spontaneous or biological oxidation to phosphine oxide, and 2) this phosphinylating agent produces acute toxic effects at a yet undefined target and genotoxic effects on derivatizing DNA leading to conversion of the deoxyguanosine moiety to 8-hydroxydeoxyguanosine. This research is necessary to ensure the safe use of phosphorus-containing insecticides.